Induction of cancer cell apoptosis by α-tocopheryl succinate:: molecular pathways and structural requirements

The vitamin E analog alpha -tocopheryl succinate (alpha -TOS) can induce apoptosis. We show that the proapoptotic activity of alpha -TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha -TOS-triggered apoptosis. More selective effecters indicated that alpha -TOS reduced PKC alpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKC alpha inhibition in alpha -TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKC alpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha -TOS-induced proapoptotic signals. Structural analogs revealed that alpha -tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha -TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.